6-amino-5-cyanomethylaminopyrimidines



United States Patent v 3 407 202 6-AMINO-5-CYANOMliTHhILAMINOPYRIMIDINESIrwin J. Pachter, Woodbury, N.Y., and Joseph Weinstock, Philadelphia,Pa., assignors to Smith Kline &

French Laboratories, Philadelphia, Pa., a corporation of RI PennsylvaniaNo Drawing. Original application June 29, 1962, Ser. No.

206,153. Divided and this application Jan, 31, 1967, R1 I, Ser. No.612,;9glaimS. (CL 260-2565) 16 R alrrtleipge sents hydrogen, loweralkyl, phenyl, thienyl or R represents hydrogen or lower alkyl, the sameor different, hydrogen is preferred; ABSTRACT OF THE DISCLOSURE Rrepresents hydrogen or an organic moiety having a 7-a minopteridines,which are useful as diuretic and hymaximum of 12 carbon atoms, such aslower alkyl, Potensive agents and as intermediates dyestuffs 01135 15halogenated lower alkyl such as trifluoromethyl, cycloamifolic acidcompounds, are prepared from 5,6-diaminolk l, al lk l, l lk l h ppyrimidines by a process with Schiff bases (6-amino-5- lower alkenyl, s-low lk p 1, methyleneaminopyrirnidines), 6-a mino 5 -'cyan0methy1-alk-ynyl, lower alkenylalkylene, cycloalkenylalkylene, aminopyrimidinesand 7-amino-dihydropteridines as interphenyl-lower alkenylalkylene,lower alkynlyalkylene, mediates. The 6-thiazolylpteridines alsohaveutility as phenyl-lower alkynylalkylene, h l thi l, f centralnervous system stimulants. The 2,4,6-triamino-5- pyrrolyl', pyrimidyl,pyridyl, quinol-yl, thiazolyl, benzyl, cyanomethylaminopyrimidines whichare intermediates phenethyl, thenyl or carbamoyl; for 7-aminopteridinesalso have diuretic activity. R corresponds to R when R; is hydrogen,lower alkyl,

halogenated lower alkyl, cycloalk-yl, lower alkenylalkylene,cycloalkenylalkylene, phenyl-lower alkenylalkyl- This application is adivisional of Ser. No. 206,153, ene, lower alkynylalkylene, phenyl-loweralk-ynylalk p filed June 29, 1962, which is a continuation-in-part ofene, phenyl, thienyl, furyl, pyrrolyl, pyrimidyl, pyridyl, SCI. NO.142,541, filed Oct. 3, 1961 and now abandoned. quinolyl, thiazglyl,benzyl phenethyl, thenyl 01- car- This invention relates to a novelprocess for the prepbamoyl and, when R is an 0:,fi-1OWC1' alkenyl, 1,5-aration of 7-aminopteridine derivatives, to novel intercycloalkenyl,phenyl n lower alkenyl, a,fi-lower mediates useful in said process andto new 7-a minopterialkynyl or phenyl-a,B-lower alkynyl, R is loweralkyl, dine derivatives prepared by said process cycloalkyl,phenyl-lower alkyl, 0:,fl-10W6I alkenyl or The 7-aminopter-idinederivatives prepared by the procphenyl-u,B-lower alkenyl respectivelyand 8 and through th intermediates which are Objects of R representshydrogen or alkali metal such as sodium or this invention are valuablepharmacodynamic agents, in potassium articular the are useful asdiuretic and hypotensive gents. Certai of these pten'dine derivativeshave been Preferred compounds of Formulas are s l ws described as potentdiuretic agents in US. Patents R represents #2,975,180 and #2,963,481.Certain of the 6-amino-5- R cyanomethylaminopyrimidines, in particularthe 2,4,6-tri- 40 amino-S-cyanomethylaminopyrimidines which are preparedby the process of this invention and are intermediates in said processfor the preparation of 7-aminopteridines have diuretic activity in theirown right. The end represenisghgnyl or products also have valuableutility as intermediates for g S y f g y i preparing other organiccompounds having utility as dye- 3 1 reprelsaen rogen phenyl thlenylstuffs or as antifolic acid compounds. In addition the 6- Pyrro y or caramoy thiazolylpteridine end products have utility as central The ariylmoieties of R R and R such as the phenyl nervous system stimulants.moiety are, optionally, inertly substituted, that is substi- The processof this invention for the preparation of 7- tuted by moieties which arenot reactive under the c0ndiaminopteridines is schematically representedas follows: tions of the process of this invention. Exemplary of inert"Formula I Formula II Formula III I HgN- -Ri B30110 HaN R1 RSCN HzN R1Iii- |i It HzN- H/C CHN R i i Formula v Formula IV H2NI i zN %N\/N\ i i1 l N R4 \N fi/ I R3 Ev 3 #107,202 Patented Oct. 22, 1968 when: I r l Rrepresents hydrogen, lower alkyl, phenyl, thienyl, carbamoyl, hydroxylor preferably substituents are lower alkyl, lower alkoxy, halogen andtrifluoromethyl.

The terms lower alkyl, lower alkenyl, lower 'alkynyl, alkylene and loweralkoxy where used herein and in the claims denote moieties having from1-6, preferably l-3, carbon atoms. The term halogenated lower alkyldenotes moieties having 1-6, preferably, 1-3 carbon atoms substituted bya halo moiety such as chloro, bromo or fluoro. The terms cycloalktyl andcycloalkenyl" denote moieties having 5-6 carbon atoms.

The pteridine products of Formula V which are objects of this inventioncould not be prepared by prior art procedures but are now available dueto this invention. These compounds have the following formula:

N N HaN R1 J U N I it R represents hydrogen, lower alkyl, phenyl,thienyl, carbamoyl, hydroxyl or in which:

Also included in this invention are the nontoxic pharmaceuticallyacceptable, acid addition salts of the above pteridines. These salts areprepared by reacting the base in an organic solvent such as ethyl ether,ethyl acetate or a lower alkanol with an excess of the acid. Exemplaryof suitable acids are hydrochloric, acetic, hydrobromic, sulfuric,phosphoric, sulfamic, ethanedisulfonic, maleic, citric, etc. acids.

The novel Schiif base and 6-amino-S-cyanomethylaminopyrimidineintermediates of Formulas II and III, respectively, are also objects ofthis invention. The acid addition salts of these compounds are furtherobjects of this invention. Such salts are prepared by reacting the baseswith an organic or inorganic acid in'a lower alkanol such as ethanol,methanol or isopropanol with isolation of the salt by cooling andfiltering. Exemplary of such salts are those prepared with maleic,citric, acetic, hydrochloric or hydrobromic acids.

The 7-amino-5,6-dihydropteridines of Formula IV are intermediates in thepreparation of the diuretic pteridines of Formula V. The position of thedouble bond in the pyrazine ring of the dihydropteridine nucleus is atpresent not definitely known. The compounds have been designated hereinin most instances as 5,6-dihydropteridines, however the compounds mayequally well be 5,8-dihydropteridines. Particularly where R is an arylmoiety, the product is likely to be the 5,8-dihydropteridine which wouldprovide conjugation of the double bond with the aryl moiety, R

It is apparent that the compound of Formula IV in which R is an cp-unsaturated moiety will readily shift a double bond to form thepteridine compounds of Formula V. Therefore the a,;8-alkenyl and-alkynyl compounds of Formula IV will isomerize to produce alkyl anda,;8-alkenyl pteridines, respectively, of Formula V.

The compounds of Formula IV in which the R moiety contains anunconjugated unsaturated bond are designated as lower alkenylalkylene,"cycloalkenylalkylene,

phenyl-lower alkenylalkylene, lower alkynylalkylene and phenyl-loweralkynylalkylene to distinguish them from the a,,8-unsaturated moieties.The distinction between the u,flunsaturated moieties and otherunsaturated groups in the process of thisinvention is the ability of theformer to isomerize to give the pteridine products, while the lattermust undergo the additional step of oxidation of 'the dihydropteridinesto form the pteridines of' Formula V.

Also included in this invention are the process and intermediates asdescribed above in which the N-atoms of the pyrazine ring of thedihydropteridines of Formula IV are substituted by lower alkyl oraralkyl moieties such as benzyl or phe'nethyll Dihydropteridines whichcontain a substituent in the 8 position are prepared as by-products ofthe cyclization of a 4-monoalkylamino-5-cyanomethylaminopyrimidine.S-substituted-dihydropteridines are prepared by reduction of the Schifl?bases of Formula II followed by reaction of the resulting5-alkylaminopyrimidine with R CHO and R CN to give the intermediateS-(alkylcyanomethylamino)pyrimidine which is then cyclized to theS-alkyldihydropteridine.

The process of this invention is most conveniently carried out withoutisolating the Schiff base intermediates of Formula II. The preparationof the 5-cyanomethylaminopyrimidines of Formula III is then accomplishedin one step as follows:

The terms R, R and R are as defined hereabove.

The starting materials for the process of this invention, namely the5,6-diaminopyrimidines of Formula I, are either known to the art-or areprepared by standard procedures such as by reduction of thecorresponding 5- nitroso compounds disclosed in US. Patent #2,975,180.The 6-amino-5-nitrosopyrimidines are reduced to the 5,6-diaminopyrimidine starting materials of Formula I by means of chemicalreducing agents or by catalytic hydrogenation.

According to the process of this invention the 5,6-diaminopyrimidine ofFormula I is reacted with at least one molar equivalent of the carbonylcompound having the formula R CHO in which R, is as defined hereabove inan inert solvent in which the reactants are substantially solublepreferably in a lower alkanol such as ethanol or methanol. The reactionmixture is preferably heated, such as on a steam bath, at about 45-90 C.for about 3-15 minutes. The Schiff base of Formula II is formed and isoptionally isolated by concentrating the mixture, filtering andrecrystallizing the solid product from a suitable solvent such as alower alkanol, for example ethanol or isopropanol. I

The Schilf base of Formula II is reacted with R CN in which R is analkali metal such as sodium or potassium or is, preferably, hydrogentogether with an acid such as a dilute mineral acidfor examplehydrochloric, sulfuric or phosphoric acids or preferably, a loweralkanoic acid such as acetic acid. A lower alkanol solvent such asethanol or methanol is advantageously added to the reaction mixture. Thereaction is preferably carried out at elevated temperature,advantageously at about 4590 C. for about 5-30 minutes. The6-amino-5-cyanomethylaminopyrimidine of Formula III is isolated from thereaction mixture by cooling and filtering.

The S-cyanomethylaminopyrimidine can be formed directly by the reactionof the 5,6-diaminopyrimidines of Formula I with a carbonyl compound,i.e., R CHO, a

cyanide compound, i.e., R CN, and an acid such as mineral acid or alower alkanoic acid at about 45 C. to about 90 C. for about 5-30minutes, R and R being as defined hereabove.

The G-amino-S-cyanomethylaminopyrimidine intermediate of Formula III istreated with an alkali metal lower alkoxide, such as sodium or potassiummethoxide or ethoxide, or an alkali metal cyanide suchas sodium orpotassium cyanide in a lower alkanol solution such as methanol orethanol solution. The reaction is preferably carried out at elevatedtemperatures such as at about 45-85 C., conveniently at the refluxtemperature of the reaction mixture. The reaction is usually allowed toproceed for about 5-10 minutes. The mixture is concentrated in vacuo togive the intermediate crude 7-amino-5,6-dihydropteridine of Formula IV,The dihydropterid ine s of Formula IV in which R is an a,p-unsaturatedmoiety rearranged directly to the pteridines of Formula V. Otherdihydropteridines are converted to the pteridines by oxidation. Thedihydro compound is air oxidized by heating in an inert solvent havingaboiling point of about 150 265 C., such as phenyl ether ordimethylformamide, conveniently at the reflux temperature of the solventand the pteridine product is isolated by cooling and filtering.Alternatively, the dihydropteridine is converted to the pteridine bytreating with an oxidizing agent such as potassium ferricyanide,potassium permanganate or, conveniently, aqueous hydrogen peroxide.

Alternatively, the cyanomethylaminopyrimidine intermediates of FormulaIII are prepared as follows:

R, R and R are as described hereabove; X is halogen, hydroxy, OSO C HOSO C H CH or and X is a reactive halogen such as bromo, chloro or iodo.

The 5,6-diaminopyrimidine is reacted with an acetonitrile derivative;i.e., ot-X-acetonitrile, in which X is as defined above, in a loweralkanol solvent such as ethanol or methanol. Advantageously, an acidbinding agent such as sodium or potassium carbonate is present in thereaction mixture. The reaction is carried out at elevated temperature,conveniently at reflux temperature of the reaction mixture, for aperiod'of about 10-60 minutes.

The following terms as used herein and in the claims are thus defined:

Lower alkanol-a straight or branched chain aliphatic alcohol having 1-6,preferably l-3, carbon atoms.

Loweralkanoic acida fatty acid having 2-4, preferably 2-3, carbon atoms.

Lower alkoxidean alkoxide moiety having 1-6, preferably 1-3, carbonatoms.

Reaction conditions other than those described are operative but withoutpraticular advantage over those described hereabove. The followingexamples will illustrate the novel process and intermediates of thisinvention and will serve to make them fully apparent to one skilled in.the art. These examples are not to be construed as limiting theoperability of this invention but, on the contrary, are indicative ofits wide scope of usefulness.

EXAMPLE 1 A mixture of 5.0 g. of 2,4,5,6-tetra-aminopyrimidinehydrochloride, 6.0 g. of benzaldehyde and 10 ml. of acetic acid isheated on a steam bath until solution is achieved. Hot absolute ethanol(75 ml.) is added and the mixture is heated to boiling. A stream ofhydrogen cyanide gas is passed into the solution for about ten minutesduring which the temperature falls to 65 C. The reaction mixture isallowed to stand at room temperature for five hours, then is filtered togive 2,4,6-triamino- 5-(a-cyanobenzylamino)pyrimidine hydrochloride,M.P. 197 C. (dec.).

Five grams of 2,4,6-triamino-5-(ct-cyanobenzylamino) pyrimidinehydrochloride, 2.5 g. of sodium methoxide and 40 ml. of methanol areheated at reflux for ten minutes. The mixture is cooled and filtered.The solid material obtained is refluxed for five minutes with 40 ml. ofphenyl ether to give, on cooling and filtering,2,4,7-triamino-6-phenylpteridine.

EXAMPLE 2 A mixture of 15.0 g. of 2,4,5,G-tetra-aminopyrimidine, 15.0 g.of benzaldehyde and 30 ml. of acetic acid is heated to obtain asolution. To this solution is added 300 ml. of hot 95% ethanol and 15.0of potassium cyanide. The mixture is refluxed for five minutes, thenallowed to stand for three hours and filtered to give2,4,6-triamino-5-(ucyanobenzylamino)pyrimidine acetate which isrecrystallized from ethyl acetate, M.P. 162-164 C. (dec.).

A 5.0 g. sample of 2,4,6-triamino-5-(oz-cyanobenzylamino)pyrimidineacetate and 2.5 g. of sodium methoxide are added to 40 ml. of methanol.The mixture is refluxed for ten minutes and then is allowed to stand foreight hours. The resulting solid material is filtered oil, then refluxedin phenyl ether solution for five minutes. Cooling and filtering gives2,4,7-triamino-6-phenylpteridine.

EXAMPLE 3 A solution of 10.0 g. of 4,5,6-triamino-2-phenylpyrimidine in75 ml. of methanol and 25 ml. of acetic acid is treated with 5.0 g. ofsodium cyanide in 25 ml. of water and 10 g. of benzaldehyde in 20 ml. ofmethanol. The mixture is allowed to stand at room temperature for about16 hours. The precipitate which forms is filtered oil? to give4,6-diamino-5-(ot cyanobenzylamino) 2 phenylpyrimidine which isrecrystallized from dimethylformamide-methanol to give yellow plates,M.P. 201203 C.

A 5.0 g. sample of4,6-diamino-5-(ct-cyanobenzylamino)-2-phenylpyrimidine, 5.0 g. of sodiummethoxide and ml. of methanol are heated at reflux for 10 minutes. Tothe hot solution is added 80 ml. of water and 10 m1. of 30% hydrogenperoxide. The mixture is allowed to stand at room temperature for fivehours. Filtration and recrystallization from methanol gives 4,7-diamino-2,6-diphenylpteridine.

EXAMPLE 4 Ten grams of 2,4,5,6-tetra-aminopyrimidine, 12.0 g. ofbenzaldehyde and 35 ml. of ethanol are heated on a steam bath for fiveminutes. Cooling and filtering gives 2,4,6-triamino-S-benzylideneaminopyrimidine. This Schiif base may be convertedto its hydrochloride salt by heating with ethanolic hydrogen chloride,then cooling and filtering.

The Schitf base prepared above is dissolved in acetic acid. Hot ethanolis added. The resulting mixture is heated to the boiling point andtreated with a stream of hydrogen cyanide gas. Working up as in Example1 gives 2,4,6-triamino-5-(a-cyanobenzylamino)pyrimidine.

Refluxing 7.5 g. of the above prerpared cyano compound with 4.2 g. ofsodium ethoxide and 60 ml. of ethanol for eight minutes, then cooling,concentrating and refluxing the residue in phenyl ether for five minutesgives, upon cooling and filtering, 2,4,7-triamino-6-phenylpteridine.

EXAMPLE 5 A mixture of 10.6 g. of p-chlorobenzaldehyde, 19.0 g. ofphenylsulfonyl chloride and 9.0 g. of potassium cyanide in 300 ml. ofethanol is heated on a steam bath for one hour. Cooling, concentratingand filtering gives p-chloro-a-cyanobenzyl phenylsulfonate.

Treating 14.0 g. of 2,4,5,6-tetra-aminopyrimidine with the aboveprepared p-chloro-a-cyanobenzyl phenylsulfonate in ethanol solutioncontaining sodium carbonate at reflux temperature for 15 minutes, gives,after cooling and filtering,2,4,6-triamino--(p-chloro-a-cyanobenzylamino) pyrimidine. In the mannerof Example 2 this pyrimidine is converted to2,4,7-triamino-6-(p-chlorophenyl)pteridine.

EXAMPLE 6 EXAMPLE 7 By the method of Example 4, using as startingmaterials in equimolar amounts in place of benzaldehyde:

formaldehyde acetaldehyde 3-chloropropionaldehyde propargyl aldehydecyclohexanecarboxaldehyde 2-quinolinecarboxaldehyde 2-furaldehyde3-phenylpropionaldehyde 5-pyrimidinecarboxaldehyde the followingcompounds are prepared:

2,4,7-triaminopteridine 2,4,7-triamino-6-methylpteridine2,4,7-triamino-6- 2-chloroethyl) pteridine2,4,7-triamino-6-vinylpteridine 2,4,7-triamino-6-cyclohexylpteridine2,4,7 -triamino-6- Z-quinolyl) pteridine 2,4,7-triamino-6- Z-furylpteridine 2,4,7-triamino-6-phenethylpteridine 2,4,7-triamino-6- (5-pyrimidyl pteridine and the corresponding dihydropteridines.

EXAMPLE 8 When the following compounds are used as starting materials inequimolar amounts in place of benzaldehyde in Example 4:

4-thiazolecarboxaldehyde 2-thiazolecarboxaldehydeS-thiazolecarboxaldehyde 2-thiopheneacetaldehydeZ-pyridinecarboxaldehyde the products obtained are respectively:

2,4,7-triamino-6-(4-thiazolyl pteridine 2,4,7-triamino-6-( Z-thiazolylpteridine 2,4,7-triamino-6- S-thiazolyl pteridine 2,4,7-triamino-6-2-thenyl pteridine 2,4,7-triamino-6- Z-pyridyl) pteridine.

EXAMPLE 9 Following the method of Example 4, 10.0 g. of 4,5,6-triamino-2-phenylpyrimidine and 5.0 g. of glyoxylamide are reacted. Uponcompletion of the steps outlined in Example 4, the intermediate4,7-diamino-5,6-dihydro-2- phenyl-6-pteridinecarboxamide is converted to4,7-diamino-2-phenyl-6-pteridinecarboxamide.

Similarly using 10.0 g. of 4,5,6-triamino-2-(Z-thienyl) pyrimidine,prepared by reduction of 4,6-diamino-5-nitroso-2-(2-thienyl)pyrimidine,and 5.0 g. of glyoxylamide in the procedure of Example 4, there isobtained 4,7-diamino-2-(2-thienyl)-6-pteridinecarboxamide.

In the same manner, 5,6-diamino-4-methylamino-2- phenylpyrimidine and5,6 diamino-4-dimethylamino-2- phenylpyrimidine, prepared by reductionof the corresponding S-nitrosopyrimidines, are reacted with glyoxylamideto give 7-amino-4-methylamino-2-phenyl-6-pteridinecarboxamide and7-amino-4-dimethylamino-Z-phenyl- -pteridinecarboxamide, respectively.

EXAMPLE 10 Reacting 15 ml. of formaldehyde with 4.0 g. of 4,5,6-triaminopyrimidine by the procedure of Example 4 gives, as the finalproduct, 4,7-diaminopteridine.

Similarly substituting benzaldehyde in place of formaldehyde yields4,7-diamino-6-phenylpteridine.

EXAMPLE 11 Ten grams of 2,4,5,6-tetra-aminopyrimidine and 7.5 g. of2-thiophenecarboxaldehyde are heated in ethanol solution for fiveminutes at 90-95 C. to give 2,4,6-triamino-5-(2-thienylmethyleneamino)pyrimidine.

A stream of hydrogen cyanide gas is passed into a dilute solution ofhydrochloric acid in ethanol containing the above prepared pyrimidine togive, after cooling and filtering, 2,4,6triamino-S-(a-cyano-2-thienylmethylamino)pyrimidine. This cyano compoundis refluxed with 3.0 g. of sodium cyanide in ethanol for five minutes togive the intermediate 2,4,7-triamino-5,8-dihydro-6-(Z-thienyl) pteridinewhich is refluxed with phenyl ether for five minutes to give2,4,7-triamino-6-(2-thienyl)pteridine.

In a similar manner using 7.5 g. of S-thiophenecarboxaldehyde as thestarting material, 2,4,7-triamino-6-(3-thienyl)pteridine is prepared.

EXAMPLE 12 A mixture of 10 g. of 2,4,5,6-tetra-aminopyrimidine, 14.0 g.of p-trifiuoromethylbenzaldehyde and 20 ml. of acetic acid is heated.The resulting solid is taken up in 1200 ml. of boiling ethanol andhydrogen cyanide gas is passed into the solution for 2-5 minutes. Themixture is filtered and allowed to stand overnight. The precipitate isisolated by filtration to give 5-(a-cyano-4-trifluoromethyl benzylamino)2,4,6 triaminopyrimidine hydrochloride which is dissolved in methanoland treated with excess sodium methoxide. The mixture is refluxed forten minutes and diluted with 200 ml. of water and 10 ml. of 30% hydrogenperoxide. The resulting mixture is refluxed for ten minutes, then cooledand filtered to give2,4,7-triamino-6-(4-trifluoromethylphenyl)pteridine.

EXAMPLE 13 By the method of Example 4, 8.0 g. of 4,5,6-triamino-2-methylpyrimidine and 5.0 g. of glyoxylamide are reacted to give4,7-diamino-2-methyl-6-pteridinecarboxamide.

In the same manner 4,7-diamino-2-ethyl-6-pteridinecarboxamide isprepared from 4,5,6-triamino-2-ethylpyrimidine and glyoxylamide.

EXAMPLE 14 A mixture of 9.0 g. of 2,4,5,6-tetra-aminopyrimidinehydrochloride in 40ml. of methanol and 25 ml. of acetic acid is heatedat 50 C. and treated first with a solution of 5 g. of sodium cyanide in17 ml. of water and then with a solution of 9.5 g. of3-cyclohexene-l-carboxaldehyde in 10 ml. of methanol. The resultingmixture is kept at 20 'C. overnight. Upon filtration there is obtained2,4,6 triamino-S-(u-cyano-3-cyclohexenylmethylamino)- pyrimidine, M.P.134l35 C.

Refluxing the above prepared cyano compound with 5.0 g. of sodiummethoxide in 80 ml. of methanol for ten minutes, adding ml. of water and12 ml. of 30% hydrogen peroxide, allowing the resulting mixture to standat room temperature, filtering and recrystallizing from methanol gives2,4,7 triamino-6-(3-cyclohexenyl)pteridine, M.P. 350 C.

Similarly reacting 2,4,5,6-terta-aminopyrimidine hydrochloride with4-pentenal, refluxing the resulting 2,4,6- triamino5-(l-cyano-4-pentenylamino)pyrimidine with sodium methoxide in metthanoland treating the resulting dihydropteridine with hydrogen peroxide gives2,4,7- triamino-6-(3-butenyl)pteridine. This material (500 mg.) indilute dimethylacetamide is reacted with hydrogen bromide gas to givethe hydrobromide salt.

In a similar manner reacting 2,4,5,6-terta-aminopyrimidine with3-hexynal gives 2,4,6-triamino-5-(lcyano-3-hexynylamino) pyrimidinewhich is refluxed with sodium methoxide in methanol. The resultingdihydropteridine is oxidized with hydrogen peroxide to give 2,4,7-triamino-6-(2-pentynyl)pteridine.

EXAMPLE A mixture of 9 g. of 2,4,5,6-terta-aminopyrimidinehydrochloride, 10 g. of cinnamaldehyde, 5 g. of sodium cyanide in 95 ml.methanol and 60 ml. of .acetic acid are reacted as in Example 14 to give2,4,6-triamino-5-(a cyanocinnamylamino)pyrirnidine, M.P. l34136 C.

A 9.3 g. sample of 2,4,6-triamino-5-(a-cyanocinnamylamino)pyrimidineacetate (prepared by treating the free base with excess acetic acid,concentrating and filtering) is added to a solution of 9.0 g. of sodiummethoxide in 200 ml. of methanol. The mixture is stirred and refluxedfor two minutes. The precipitate was collected, washed with methanol,dried and recrystallized from ethanol to give2,4,7-triamino-6-fl-phenethylpteridine, M.P. 296- 298 C. (dec.).

EXAMPLE 16 A solution of 9 g. of 2,4,5,6-tetra-aminopyrimidinehydrochloride in 45 ml. methanol and 45 ml. acetic acid is treated with5 g. of sodium cyanide in 20 ml. of water and 10 g. ofphenylproparglylaldehyde in 10 ml. of methanol. The mixture is heated to50 C., then cooled for three hours at 7 C. On filtering there isobtained 2,4,6 triamino 5 (a-cyano-'y-phenylpropargylamino)- pyrimidine.

T o a solution of 6.0 g. of sodium methoxide in 125 ml. of methanol isadded 6.0 g. of2,4,6-triamino-5-(at-cyanoy-phenylproparglyamio)pyrimidine. The mixtureis refluxed for three minutes, then cooled and filtered. The solidproduct is recrystallized from ethanol to give 2,4,7-triamino-6-styrylpteridine, M.P. 345347 C. (dec.).

One gram of 2,4,7-triamino-6-styrylpteridine is dissolved in dilutehydrochloric acid to give, on cooling and filtering, the hydrochloridesalt.

EXAMPLE 17 A solution of 36 g. of 2,6-dichloro-5nitro-4-pyrimidinecarboxylic acid methyl ester in 720 m1. of 10% ammonia in methanol isheated in an autoclave at 100 C. For six hours. The mixture is allowedto stand overnight, then is evaporated and the residue is dissolved indilute hydrochloric acid. Adding ammonia, filtering the precipitate andrecrystallizing it from dimethylformamide gives 2,6-diamino-4-carbamoyl-5-nitropyrimidine.

A mixture of 1.0 g. of 2,6-diamino-4-carbamoyl-5- nitropyrimidine, 200m1. of methanol and /2 teaspoon of Raney nickel catalyst ishydrogenated. The resulting mixture is filtered and the alcohol isevaporated from the filtrate, The residue is recrystallized from waterto give 2,5,6-triamino-4-carbamoylpyrimidine, M.P. 286-288 C. (dec.).

A sample of 2,5,6-triamino-4-carbamoylpyrimidine in methanol and aceticacid is heated to 50 C. and treated with aqueous sodium cyanide andbenzaldehyde in methanol to give 2,6-diamino 4carbamoyl-5-(u-cyanobenzylamino)pyrimidine. Refluxing this pyrimidinewith sodium methoxide in methanol for 10 minutes, adding aqueoushydrogen peroxide to the solution and allowing it to stand at roomtemperature for five hours gives, after filtering and recrystallizing inmethanol, 2,7-diamino-4- carbamoyl-6-phenylpteridine.

EXAMPLE 18 EXAMPLE 19 By the procedure of Example 1, 10 g. of2,5,6-triaminopyrimidine is reacted with slight excess of one molarequivalent of benzaldehyde in acetic acid and absolute ethanol. A streamof hydrogen cyanide gas is passed into the solution and after working upas in Example 1 there is obtained 2,6-diamino-5-(a-cyanobenzylamino)pyrimidine. Refluxing this pyrimidine with sodium methoxide in methanoland treating the resulting dihydropteridine with hydrogen peroxide gives2,7-diamino-G-phenylpteridine.

Similarly reacting molar equivalent amounts of 2,5,6-triamino-4-methylpyrimidine and 2,5,6-triamino-4-pyrimidinol withbenzaldehyde, treating with hydrogen cyanide gas refluxing the resultingcyano intermediate with sodium methoxide in methanol and oxidizing theintermediate dihydropteridine with hydrogen peroxide gives 2,7-diamino-4-methyl-G-phenylpteridine and 2,7-diamino-4-hydroxy- 6-phenylpteridine,respectively.

EXAMPLE 20 2,5,6-triamio-4-phenylpyrimidine is prepared as follows:

Known 2 amino 4 phenyl 6 hydroxypyrimidine is coupled withbenzenediazonium chloride in aqueous solution at the 5-position. The6-hydroxy compound is converted to a 6-chloro cmopound with phosphorousoxychloride then reacted with butanolic ammonia to form the 6-amine. Thecoupled diazonium moiety is then removed by catalytic reduction to givethe desired triamino compound, M.P. 220-222" C.

A mixture of 20 g. of 2,5,6-triamino-4-phenylpyrimidine in methanolicacetic acid at 5 0 C. is treated with an aqueous solution of 6 g. ofsodium cyanide then with a methanol solution of 7.5 g. of glyoxylamide.The resulting mixture is cooled and filtered to give 2,6-diamino-5-(ot-cyanocarbamoylmethylamino)-4-phenylpyrimidine.

The above prepared cyano compound is refluxed with sodium methoxide inmethanol then treated with aqueous hydrogen peroxide to give2,7-diamino-4-phenyl-6-pteridine carboxamide.

What is claimed is:

1. A chemical compound of the class consisting of a free base and itsacid addition salts, said free base having the following formula:

in which:

R is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, thienyl, carbamoyl, hydroxyl and R is a member selectedfrom the group consisting of hydrogen, lower alkyl, phenyl, thienyl andamino; R is a member selected from the group consisting of hydrogen andlower alkyl; and R is a member selected from the group consisting ofhydrogen, lower alkyl, halogenated lower alkyl, cycloalkyl, 11,}3-10W6I'alkenyl, a, 8-cycloalkenyl, phenyla, 3-lower alkenyl, a,,8-loweralkynyl, phenyl-afilower alkynyl, lower alkenylalkylene,cycloalkenylalkylene, phenyl-lower alkenylalkylene, loweralkynylalkylene, phenyl-lower alkynylalkylene, phenyl, thienyl, furyl,pyrrolyl, pyrimidyl, pyridyl, quinolyl, thiazolyl, benzyl, phenethyl,thenyl and carbamoyl, said cycloalkyl and cycloalkenyl having 5-6 carbonatoms. 2. A chemical compound according to claim 1 in which R and R areamino and R is phenyl.

3. A chemical compound according to claim 1 in which R and R are aminoand R is thienyl.

4. A chemical compound according to claim 1 in which R and R are aminoand R is phenyl as a pharmaceutically acceptable acid addition salt.

5. A chemical compound according to claim 1 in which R and R are aminoand R is phenyl as the monoacetate salt.

6. A chemical compound according to claim 1 in which R and R are aminoand R is benzyl.

7. 2,4,6 triamino-S {on-cyano-l-methy1-2-pyrrolylmethylamino)pyrimidine.

Traube et al.: Berichte, vol. 39 (1906), pp. 227-35. Wagner et al.:Synthetic Organic Chemistry, 1953, pp. 606-7.

NICHOLAS S. RIZZO, Primary Examiner.

ALEX MAZEL, R. GALLAGHER, Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,407,202 October 22, 1968 Irwin J. Pachter et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 10, lines 62 to 67, the formula should appear as shown below:

Signed and sealed this 3rd day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

